About 7.9 million women and 4.6 million men in the US suffer from interstitial cystitis/bladder pain syndrome (IC/BPS). For many patients, the currently available treatments are inadequate and prone to adverse side effects, including potential dependence and abuse of prescription painkillers. An innovative nonpharmacological approach is proposed here to treat the debilitating condition of IC/BPS using a newly developed chemical genetics technology called RELIEPH (Receptor Engineering to Lessen Inflammation-Evoked Pain and Hyperactivity). The technology, which is based on the same principles as optogenetics and DREADD, will install engineered chloride (Cl?) channels into urothelial cells and peripheral nociceptors to control bladder hyperactivity and to alleviate pain in IC/BPS. The central hypothesis is that the expression of non-native Cl? channels in the neuron-like urothelial cells and in peripheral nerves can dynamically re-set the hypersensitization of the peripheral afferents without affecting the process of normal nociception. Two different types of ?chemical genetic? designs will be tested in a rat model of IC/BPS. The first type acts passively by sensing inflammatory conditions such as acidosis in urothelial cells and peri-nerve tissues. Since etiology of IC/BPS is still unknown and inflammation is not always present, the second type is designed to selectively respond to small natural chemicals (including metabolites of certain food) that would otherwise have little or no analgesic action without the engineered Cl? channels. Promising preliminary data have demonstrated the efficacy of one of engineered channels in treating inflammatory pain and in restoring three outcome measures (intercontraction intervals, peak micturition pressure, and micturition pressure threshold) in a rat model of IC/BPS. The specific aims for the proposed new studies are: (1) design and optimize ligand-gated Cl? channels to be activated or modulated by primary and secondary amines found in common food; (2) quantify the physiological effects of the engineered Cl? channels in urothelial cell cultures by measuring ATP release and intracellular Ca2+; (3) devise and optimize effective gene delivery strategies by bladder instillation and peri-nerve injection using rAAV, liposomes, and functionalized nanoparticles, and quantify the engineered receptor expression and localization in urothelial cells and innervating afferents; and (4) evaluate the in vivo treatment efficacies and gene dose dependence to devise strategies to improve outcomes. The innovative idea and bold approaches proposed here will lead to the development of fundamentally new IC/BPS therapy that will greatly and effectively improve chronic pain management and reduce the risk of prescription drug abuse.